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D. Subramaniam



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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-026 - Final Results of a Phase 2 Trial of the Oncolytic Virus Reovirus Serotype 3-Dearing Strain (REOLYSIN®) in Metastatic NSCLC Patients with a Ras-activated Pathway. (ID 1994)

      09:30 - 09:30  |  Author(s): D. Subramaniam

      • Abstract

      Background
      Reovirus is a naturally occurring virus which preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. In preclinical studies, reovirus induces cell cycle arrest, acting synergistically with standard cytotoxic agents. We have hypothesized that patients with EGFR-mutated, EGFR-amplified, BRAF or Kras-mutated NSCLC should all have a common downstream activated Ras pathway and should be susceptible to treatment with reovirus.

      Methods
      We conducted a Fleming, single-arm, phase II study to evaluate safety and the objective response rate (primary end-points), as well as 6-month progression-free and 1 year survival (secondary end-points) of metastatic NSCLC patients treated with reovirus in combination with paclitaxel/carboplatin (P/C). Eligible patients had ECOG PS 0-2, adequate organ function, no prior chemotherapy for metastatic disease, and tumors with the specified above genotype, as per CLIA certified laboratory testing. Prior adjuvant chemotherapy, or erlotinib/gefitinib for pts with EGFR-mutant tumors was permitted. Patients received Reovirus (3 x 10[10 ]TCID~50~) intravenously daily on days 1-5, in combination with P/C at initial doses of P 200 mg/m[2] and C AUC 6, on day 1 of each 21-day cycle. Due to exacerbation of prior colitis and febrile neutropenia (1 each) in the first two pts, doses were subsequently reduced to P 175 mg/m m[2] and C AUC 5.

      Results
      Overall, 37 patients received 209 cycles (per pt median 4, range 1 to 18). Grade 3-4 toxicity included febrile neutropenia (3 pts), G3 diarrhea (2 pts), G3 anemia (8 pts), fatigue in 6 pts (5 G3, 1 G4), nausea/vomiting and thrombocytopenia (2 pts each), electrolyte abnormalities, and single G3 episodes of arthralgia and transaminitis. Molecular tumor demographics included: 20 Kras (2 G12A, 9 G12C, 1 G12D, 1 G12R, 1 G12S, 3 G12V, 1 G13C, 1 G13R, 1 G12C/V double mutant), 3 EGFR exon 19, 4 BRAF V600E mutations, and 10 EGFR amplified only. Response evaluation showed 11 RECIST partial responses (30%) (EGFR amp 5, BRAF 2, Kras 3, EGFR mut 1), 21 SD, and 4 PD. PFS (by CT and PET) at 6 months for 36 patients with enough follow up to date is 36%, with PET results influencing switching to second line therapy in several patients with SD by CT. Sixteen patients received 6 or more cycles. One year survival was 53%.

      Conclusion
      Reovirus can be administered safely in combination with P/C and patient selection by Ras-activated pathway is feasible in the clinical setting. Overall clinical efficacy is encouraging. Randomized evaluation is planned.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-003 - Correlative Analysis of Circulating Biomarkers from a Phase 1b/2 trial of Cabozantinib (C) with or without Erlotinib (E) in Patients (Pts) with Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) (ID 266)

      09:30 - 09:30  |  Author(s): D. Subramaniam

      • Abstract

      Background
      Cabozantinib (C) is a potent ATP-competitive inhibitor of MET and vascular endothelial growth factor receptor 2 (VEGFR2) along with KIT, RET, AXL, TIE2, and FLT3. Hepatocyte growth factor (HGF), the ligand of MET, and VEGF act synergistically to promote angiogenesis. There are currently no widely accepted prognostic or predictive biomarkers for anti-angiogenic agents.

      Methods
      This is a retrospective correlative biomarker study from the phase 1b/2 trial of C+/-E in stage IIIB-IV NSCLC. All pts had to fail prior therapy with E. Both drugs are oral and dosed daily. C dosing is in the free-base equivalent weight. In phase I, there was a 2 week lead in with E and the cohorts included: 1A (60 mg C+150 mg E), 2A (60 mg C+100 mg E), 3A (100 mg C+100 mg E), 4A (100 mg C+50 mg E), and 2B (40 mg C+150 mg E). In phase II, both drugs started simultaneously: Arm A (100 mg C) and Arm B (100 mg C+50 mg E). Pts were included in the study if a pre-E+C and post-C > day 29 plasma sample was available. The Milliplex 13-plex and Luminex 51-plex assays were used. For this preliminary analysis, select markers previously implicated in angiogenesis (bFGF, VEGF, sVEGFR1-3, IL-6, IL-8, IL-12, IL-17, PDGF-BB, ICAM-1, VCAM-1) and those of interest (ligands of KIT and MET- SCF and HGF, respectively) were analyzed. Log transformed mean fluorescence intensity (MFI) values and Wilcoxon Rank paired sum tests were used to detect changes from day 1-29. A change from baseline was noted to be significant if at least 15% (median) with α<0.05 (2-sided) and a trend if 10-15% (median) with α<0.08 (2-sided).

      Results
      73 pts included: 52 phase I and 21 phase II; median age 60 years; 23M/50F; 56.2% nonsmoker; 91.8% adenocarcinomas. The pts with samples from both time points were divided into two groups due to limited sample size and included: Group R (complete/partial response and stable disease> 6 months; n=22) and Group NR (stable disease< 6 months and progressive disease; n=51). The only marker that changed in a single direction in all subjects within a group was sVEGFR2 in group R. Overall, significant decreases were noted in sVEGFR1-3, IL-6, PDGF-BB, and trended in IL12p70 and IL-17. By subgroups: Group R had significant decreases in bFGF, VEGF, sVEGFR1-3, IL-6, IL-8, IL-12(p40+p70), IL-17, PDGF-BB, SCF, and trended in HGF (median 10.1% ↓, p=0.0275); and Group NR had significant decreases in sVEGFR2-3, IL-6, PDGF-BB, and trended in sVEGFR-1, IL-6, and IL-17.

      Conclusion
      Both groups R+NR had a decrease in sVEGFR-2, suggesting that this is a marker of treatment with C rather than a marker of response. However, overall group R had larger dynamic decreases of immune markers than group NR. HGF, which is targeted downstream by C and plays a role in angiogenesis and E resistance, had a trend to decrease in group R but not group NR. This study is retrospective with a small sample size, imbalanced numbers per response subgroup, and is exploratory in nature.